Pub Date : 2006-12-01DOI: 10.1177/09680519060120060801
J. Bell, I. Botos, P. Hall, J. Askins, J. Shiloach, D. Davies, D. Segal
Toll-like receptors (TLRs), type I integral membrane receptors, recognize pathogen associated molecular patterns (PAMPs). PAMP recognition occurs via the N-terminal ectodomain (ECD) which initiates an inflammatory response that is mediated by the C-terminal cytosolic signaling domain. To understand the molecular basis of PAMP recognition, we have begun to define TLR—ECD structurally. We have solved the structure of TLR3-ECD, which recognizes dsRNA, a PAMP associated with viral pathogens. TLR3-ECD is a horseshoe-shaped solenoid composed of 23 leucine-rich repeats (LRRs). The regular LRR surface is disrupted by two insertions at LRR12 and LRR20 and 11 N-linked carbohydrates. Of note, one side of the ECD is carbohydrate-free and could form an interaction interface. We have shown that TLR3-ECD binds directly to pI:pC, a synthetic dsRNA ligand, but not to p(dI):p(dC). Without a TLR3—dsRNA complex structure, we can only speculate how ligand binds. Analysis of the unliganded structure reveals two patches of basic residues and two binding sites for phosphate backbone mimics, sulfate ions, that may be capable of recognizing ligand. Mutational and co-crystallization studies are currently underway to determine how TLR3 binds its ligand at the molecular level.
{"title":"The molecular structure of the TLR3 extracellular domain","authors":"J. Bell, I. Botos, P. Hall, J. Askins, J. Shiloach, D. Davies, D. Segal","doi":"10.1177/09680519060120060801","DOIUrl":"https://doi.org/10.1177/09680519060120060801","url":null,"abstract":"Toll-like receptors (TLRs), type I integral membrane receptors, recognize pathogen associated molecular patterns (PAMPs). PAMP recognition occurs via the N-terminal ectodomain (ECD) which initiates an inflammatory response that is mediated by the C-terminal cytosolic signaling domain. To understand the molecular basis of PAMP recognition, we have begun to define TLR—ECD structurally. We have solved the structure of TLR3-ECD, which recognizes dsRNA, a PAMP associated with viral pathogens. TLR3-ECD is a horseshoe-shaped solenoid composed of 23 leucine-rich repeats (LRRs). The regular LRR surface is disrupted by two insertions at LRR12 and LRR20 and 11 N-linked carbohydrates. Of note, one side of the ECD is carbohydrate-free and could form an interaction interface. We have shown that TLR3-ECD binds directly to pI:pC, a synthetic dsRNA ligand, but not to p(dI):p(dC). Without a TLR3—dsRNA complex structure, we can only speculate how ligand binds. Analysis of the unliganded structure reveals two patches of basic residues and two binding sites for phosphate backbone mimics, sulfate ions, that may be capable of recognizing ligand. Mutational and co-crystallization studies are currently underway to determine how TLR3 binds its ligand at the molecular level.","PeriodicalId":80292,"journal":{"name":"Journal of endotoxin research","volume":"12 1","pages":"375 - 378"},"PeriodicalIF":0.0,"publicationDate":"2006-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/09680519060120060801","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"65208829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-12-01DOI: 10.1177/09680519060120060701
R. Kitz, M. Rose, A. Borgmann, R. Schubert, S. Zielen
Background: Inhaled endotoxin is known to induce airway inflammation, causing bronchial hyper-reactivity. Objective: We characterized the response to lipopolysaccharide-inhalation by measuring exhaled nitric oxide (eNO) and inflammatory mediators. Patients and Methods : A total of 43 adult volunteers (13 asthmatics, 30 healthy controls) inhaled stepwise LPS every 30 min up to a cumulative dose of 100 µg (2.5, 10.5, 42, 45 µg). After each provocation and up to 24 h later, FEV1 was determined; the procedure was stopped when FEV1 declined more than 12.5%. We measured eNO, leucocytes, eosinophils, polymorphonuclear neutrophils (PMNs), C-reactive protein (CrP), lipopolysaccharide binding protein (LBP), eosinophilic cationic protein (ECP), leucotriene B4 (LTB4), thromboxane B2 (TXB2), and body temperature. Results: Initial eNO values were higher in asthmatics (P < 0.01), but only increased in an asthmatic subgroup. Marked differences were observed in the systemic response to LPS inhalation. Significant increases were found for CrP, LBP, and PMNs. There was no correlation between FEV1 decrease and basal eNO levels. Conclusions: Inhalation of endotoxin was followed by clinical and laboratory signs of systemic inflammation, with asthmatics responding to the challenge similar as healthy subjects. Bronchial eNO increased only temporarily in asthmatics.
{"title":"Systemic and bronchial inflammation following LPS inhalation in asthmatic and healthy subjects","authors":"R. Kitz, M. Rose, A. Borgmann, R. Schubert, S. Zielen","doi":"10.1177/09680519060120060701","DOIUrl":"https://doi.org/10.1177/09680519060120060701","url":null,"abstract":"Background: Inhaled endotoxin is known to induce airway inflammation, causing bronchial hyper-reactivity. Objective: We characterized the response to lipopolysaccharide-inhalation by measuring exhaled nitric oxide (eNO) and inflammatory mediators. Patients and Methods : A total of 43 adult volunteers (13 asthmatics, 30 healthy controls) inhaled stepwise LPS every 30 min up to a cumulative dose of 100 µg (2.5, 10.5, 42, 45 µg). After each provocation and up to 24 h later, FEV1 was determined; the procedure was stopped when FEV1 declined more than 12.5%. We measured eNO, leucocytes, eosinophils, polymorphonuclear neutrophils (PMNs), C-reactive protein (CrP), lipopolysaccharide binding protein (LBP), eosinophilic cationic protein (ECP), leucotriene B4 (LTB4), thromboxane B2 (TXB2), and body temperature. Results: Initial eNO values were higher in asthmatics (P < 0.01), but only increased in an asthmatic subgroup. Marked differences were observed in the systemic response to LPS inhalation. Significant increases were found for CrP, LBP, and PMNs. There was no correlation between FEV1 decrease and basal eNO levels. Conclusions: Inhalation of endotoxin was followed by clinical and laboratory signs of systemic inflammation, with asthmatics responding to the challenge similar as healthy subjects. Bronchial eNO increased only temporarily in asthmatics.","PeriodicalId":80292,"journal":{"name":"Journal of endotoxin research","volume":"12 1","pages":"367 - 374"},"PeriodicalIF":0.0,"publicationDate":"2006-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/09680519060120060701","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"65208818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-12-01DOI: 10.1177/09680519060120060201
Y. Knirel, Olga V. Bystrova, N. A. Kocharova, U. Zähringer, G. Pier
The review is devoted to recent progress in the structural elucidation of the lipopolysaccharide of the bacterium Pseudomonas aeruginosa, including O-antigen biological repeats, core oligosaccharide, and lipid A. Data on biosynthesis, genetics and serology of the lipopolysaccharide isolated from various P. aeruginosa O-serogroups are discussed in relation to the chemical structures.
{"title":"Review: Conserved and variable structural features in the lipopolysaccharide of Pseudomonas aeruginosa","authors":"Y. Knirel, Olga V. Bystrova, N. A. Kocharova, U. Zähringer, G. Pier","doi":"10.1177/09680519060120060201","DOIUrl":"https://doi.org/10.1177/09680519060120060201","url":null,"abstract":"The review is devoted to recent progress in the structural elucidation of the lipopolysaccharide of the bacterium Pseudomonas aeruginosa, including O-antigen biological repeats, core oligosaccharide, and lipid A. Data on biosynthesis, genetics and serology of the lipopolysaccharide isolated from various P. aeruginosa O-serogroups are discussed in relation to the chemical structures.","PeriodicalId":80292,"journal":{"name":"Journal of endotoxin research","volume":"12 1","pages":"324 - 336"},"PeriodicalIF":0.0,"publicationDate":"2006-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/09680519060120060201","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"65208638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-12-01DOI: 10.1177/09680519060120060601
F. Porta, J. Takala, C. Weikert, P. Kaufmann, S. Krahenbuhl, S. Jakob
Mitochondrial dysfunction may contribute to impaired oxygen metabolism during experimental and clinical sepsis. 1–5 In normal conditions, mitochondrial oxygen consumption is well coupled to ATP synthesis: electron transport through the respiratory chain complexes creates a proton gradient across the inner membrane, essential for final ATP synthesis. The efficiency of mitochondrial respiration is dependent on the function of the respiratory chain enzyme complexes and on the structural integrity of the inner mitochondrial membrane. It has been proposed that during endotoxemia, direct inhibition of complex I of the respiratory chain by nitric oxide4 and proton leak across the inner mitochondrial membrane 1 can contribute to impaired mitochondrial respiration and less efficient energy production. While the first mechanism indicates reduced oxygen consumption and ATP production, the latter mechanism implies oxygen use not related to energy production, and hence, reduced production of ATP per unit of oxygen consumed. Catecholamines are used to support hemodynamics in septic patients. While these drugs improve the supply of
{"title":"Effect of endotoxin, dobutamine and dopamine on muscle mitochondrial respiration in vitro","authors":"F. Porta, J. Takala, C. Weikert, P. Kaufmann, S. Krahenbuhl, S. Jakob","doi":"10.1177/09680519060120060601","DOIUrl":"https://doi.org/10.1177/09680519060120060601","url":null,"abstract":"Mitochondrial dysfunction may contribute to impaired oxygen metabolism during experimental and clinical sepsis. 1–5 In normal conditions, mitochondrial oxygen consumption is well coupled to ATP synthesis: electron transport through the respiratory chain complexes creates a proton gradient across the inner membrane, essential for final ATP synthesis. The efficiency of mitochondrial respiration is dependent on the function of the respiratory chain enzyme complexes and on the structural integrity of the inner mitochondrial membrane. It has been proposed that during endotoxemia, direct inhibition of complex I of the respiratory chain by nitric oxide4 and proton leak across the inner mitochondrial membrane 1 can contribute to impaired mitochondrial respiration and less efficient energy production. While the first mechanism indicates reduced oxygen consumption and ATP production, the latter mechanism implies oxygen use not related to energy production, and hence, reduced production of ATP per unit of oxygen consumed. Catecholamines are used to support hemodynamics in septic patients. While these drugs improve the supply of","PeriodicalId":80292,"journal":{"name":"Journal of endotoxin research","volume":"12 1","pages":"358 - 366"},"PeriodicalIF":0.0,"publicationDate":"2006-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/09680519060120060601","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"65208766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-12-01DOI: 10.1177/09680519060120060301
E. Lowe, T. M. Doherty, H. Karahashi, M. Arditi
Signaling by Toll-like receptors (TLRs) has attracted accelerating attention over the past decade because of the central role of TLR signaling in both innate and adaptive immunity. In addition, TLR signaling is now increasingly implicated in a remarkably wide range of diseases that are either caused, or accompanied, by dysregulated inflammation. Much has been learned about the basic signaling framework and participants, as well as how signaling is turned off and fine-tuned. Here, we summarize key aspects of TLR signaling, focusing on interaction with the anti-inflammatory TGF-β signaling network. We propose that ubiquitination and de-ubiquitination of TLR pathway components may be a mechanism by which predominantly anti-inflammatory input is integrated into the host response to fine-tune inflammation in accordance with the needs of host defenses.
{"title":"Review: Ubiquitination and de-ubiquitination: role in regulation of signaling by Toll-like receptors","authors":"E. Lowe, T. M. Doherty, H. Karahashi, M. Arditi","doi":"10.1177/09680519060120060301","DOIUrl":"https://doi.org/10.1177/09680519060120060301","url":null,"abstract":"Signaling by Toll-like receptors (TLRs) has attracted accelerating attention over the past decade because of the central role of TLR signaling in both innate and adaptive immunity. In addition, TLR signaling is now increasingly implicated in a remarkably wide range of diseases that are either caused, or accompanied, by dysregulated inflammation. Much has been learned about the basic signaling framework and participants, as well as how signaling is turned off and fine-tuned. Here, we summarize key aspects of TLR signaling, focusing on interaction with the anti-inflammatory TGF-β signaling network. We propose that ubiquitination and de-ubiquitination of TLR pathway components may be a mechanism by which predominantly anti-inflammatory input is integrated into the host response to fine-tune inflammation in accordance with the needs of host defenses.","PeriodicalId":80292,"journal":{"name":"Journal of endotoxin research","volume":"12 1","pages":"337 - 345"},"PeriodicalIF":0.0,"publicationDate":"2006-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/09680519060120060301","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"65208693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-12-01DOI: 10.1177/09680519060120060401
N. Koide, A. Morikawa, Hiroyasu Ito, T. Sugiyama, F. Hassan, S. Islam, G. Tumurkhuu, I. Mori, T. Yoshida, T. Yokochi
Previously, we found that mouse TH2.52 cells possess the characteristic of CD5+ B1 cells and proliferate in response to lipopolysaccharide (LPS). The effect of LPS on cytokine production by TH2.52 B1 cells was studied. TH2.52 cells constitutively produced a small amount of tumor necrosis factor (TNF)-α and interleukin (IL)-6, and TNF-α and IL-6 production was markedly enhanced by LPS stimulation. Although interferon (IFN)-γ caused the production of various cytokines, such as IL-2, IL-4, IL-6 and TNF-α in TH2.52 cells, LPS did not cause the production of such cytokines. LPS did not induce IFN-β production in TH2.52 cells and TH2.52 cells lacked the expression of several molecules participating in the MyD88-independent pathway in LPS signaling. Defective responsiveness of TH2.52 B1 cells to LPS in cytokine production might be responsible for the failure of IFN-β production due to the lack of molecules participating in the MyD88-independent pathway.
{"title":"Defective responsiveness of CD5+ B1 cells to lipopolysaccharide in cytokine production","authors":"N. Koide, A. Morikawa, Hiroyasu Ito, T. Sugiyama, F. Hassan, S. Islam, G. Tumurkhuu, I. Mori, T. Yoshida, T. Yokochi","doi":"10.1177/09680519060120060401","DOIUrl":"https://doi.org/10.1177/09680519060120060401","url":null,"abstract":"Previously, we found that mouse TH2.52 cells possess the characteristic of CD5+ B1 cells and proliferate in response to lipopolysaccharide (LPS). The effect of LPS on cytokine production by TH2.52 B1 cells was studied. TH2.52 cells constitutively produced a small amount of tumor necrosis factor (TNF)-α and interleukin (IL)-6, and TNF-α and IL-6 production was markedly enhanced by LPS stimulation. Although interferon (IFN)-γ caused the production of various cytokines, such as IL-2, IL-4, IL-6 and TNF-α in TH2.52 cells, LPS did not cause the production of such cytokines. LPS did not induce IFN-β production in TH2.52 cells and TH2.52 cells lacked the expression of several molecules participating in the MyD88-independent pathway in LPS signaling. Defective responsiveness of TH2.52 B1 cells to LPS in cytokine production might be responsible for the failure of IFN-β production due to the lack of molecules participating in the MyD88-independent pathway.","PeriodicalId":80292,"journal":{"name":"Journal of endotoxin research","volume":"12 1","pages":"346 - 351"},"PeriodicalIF":0.0,"publicationDate":"2006-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/09680519060120060401","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"65208710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-12-01DOI: 10.1177/09680519060120060501
P. Thomas, D. Lazure, R. Moussa, O. Bajenova, P. Burke, A. Ganguly, R. Armour Forse
Using a combination of gel-exclusion chromatography and ligand binding with [125I]-lipopolysaccharide (LPS), we discovered two novel endotoxin-binding proteins, p31LPB and p34LPB, in Kupffer cells. Their molecular masses suggest that these are previously undescribed LPS-binding proteins (LBPs). Evidence from detergent-based cell extractions shows that these proteins are probably transmembrane or located on the inner leaflet of the lipid bilayer. We have partially purified the proteins from detergent extracts of Kupffer cells and proven that they bind diphosphoryl lipid A, an interaction associated with TNF-α production. The proteins do not bind monophosphoryl lipid A. Diphosphoryl lipid A binding occurs in the absence of serum, suggesting a mechanism of cytokine production distinct from that involving CD14 and lipopolysaccharide-binding protein (LPB). The two proteins were not detectable in resident peritoneal macrophages or in a number of other cell lines of the macrophage/monocyte lineage, suggesting specificity towards terminally differentiated macrophages such as Kupffer cells.
{"title":"Identification of two novel LPS-binding proteins in Kupffer cells: implications in TNF-α production","authors":"P. Thomas, D. Lazure, R. Moussa, O. Bajenova, P. Burke, A. Ganguly, R. Armour Forse","doi":"10.1177/09680519060120060501","DOIUrl":"https://doi.org/10.1177/09680519060120060501","url":null,"abstract":"Using a combination of gel-exclusion chromatography and ligand binding with [125I]-lipopolysaccharide (LPS), we discovered two novel endotoxin-binding proteins, p31LPB and p34LPB, in Kupffer cells. Their molecular masses suggest that these are previously undescribed LPS-binding proteins (LBPs). Evidence from detergent-based cell extractions shows that these proteins are probably transmembrane or located on the inner leaflet of the lipid bilayer. We have partially purified the proteins from detergent extracts of Kupffer cells and proven that they bind diphosphoryl lipid A, an interaction associated with TNF-α production. The proteins do not bind monophosphoryl lipid A. Diphosphoryl lipid A binding occurs in the absence of serum, suggesting a mechanism of cytokine production distinct from that involving CD14 and lipopolysaccharide-binding protein (LPB). The two proteins were not detectable in resident peritoneal macrophages or in a number of other cell lines of the macrophage/monocyte lineage, suggesting specificity towards terminally differentiated macrophages such as Kupffer cells.","PeriodicalId":80292,"journal":{"name":"Journal of endotoxin research","volume":"12 1","pages":"352 - 357"},"PeriodicalIF":0.0,"publicationDate":"2006-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/09680519060120060501","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"65208757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-10-01DOI: 10.1177/09680519060120050201
J. Andrä, T. Gutsmann, P. Garidel, K. Brandenburg
A basic challenge in the treatment of septic patients in critical care units is the release of bacterial pathogenicity factors such as lipopolysaccharide (LPS, endotoxin) from the cell envelope of Gram-negative bacteria due to killing by antibiotics. LPS aggregates may interact with serum and membrane proteins such as LBP (lipopolysaccharide-binding protein) and CD14 leading to the observed strong reaction of the immune system. Thus, an effective treatment of patients infected by Gram-negative bacteria must comprise beside bacterial killing the neutralization of endotoxins. Here, data are summarized for synthetic compounds indicating the stepwise development to very effective LPS-neutralizing agents. These data include synthetic peptides, based on the endotoxin-binding domains of natural binding proteins such as lactoferrin, Limulus anti-LPS factor, NK-lysin, and cathelicidins or based on LPS sequestering polyamines. Many of these compounds could be shown to act not only in vitro, but also in vivo (e.g . in animal models of sepsis), and might be useful in future clinical trials and in sepsis therapy.
{"title":"Invited review: Mechanisms of endotoxin neutralization by synthetic cationic compounds","authors":"J. Andrä, T. Gutsmann, P. Garidel, K. Brandenburg","doi":"10.1177/09680519060120050201","DOIUrl":"https://doi.org/10.1177/09680519060120050201","url":null,"abstract":"A basic challenge in the treatment of septic patients in critical care units is the release of bacterial pathogenicity factors such as lipopolysaccharide (LPS, endotoxin) from the cell envelope of Gram-negative bacteria due to killing by antibiotics. LPS aggregates may interact with serum and membrane proteins such as LBP (lipopolysaccharide-binding protein) and CD14 leading to the observed strong reaction of the immune system. Thus, an effective treatment of patients infected by Gram-negative bacteria must comprise beside bacterial killing the neutralization of endotoxins. Here, data are summarized for synthetic compounds indicating the stepwise development to very effective LPS-neutralizing agents. These data include synthetic peptides, based on the endotoxin-binding domains of natural binding proteins such as lactoferrin, Limulus anti-LPS factor, NK-lysin, and cathelicidins or based on LPS sequestering polyamines. Many of these compounds could be shown to act not only in vitro, but also in vivo (e.g . in animal models of sepsis), and might be useful in future clinical trials and in sepsis therapy.","PeriodicalId":80292,"journal":{"name":"Journal of endotoxin research","volume":"12 1","pages":"261 - 277"},"PeriodicalIF":0.0,"publicationDate":"2006-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/09680519060120050201","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"65208481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-10-01DOI: 10.1177/09680519060120050501
M. C. González-León, Alessandra Soares-Schanoski, C. del Fresno, A. Cimadevila, V. Gómez-Piña, E. Mendoza-Barberá, Felipe García, E. Marín, F. Arnalich, P. Fuentes-Prior, E. López-Collazo
In contrast to the thoroughly characterized mechanisms of positive regulation within cytokine signaling pathways, our knowledge of negative feedback loops is comparatively sparse. We and others have previously reported that IRAK-M down-regulates inflammatory responses to multiple stimuli. In particular, we could show that the nitric oxide (NO) donor, GSNO, induces IRAK-M overexpression in human monocytes. Here we study the expression of another important negative regulator of cytokine signaling, SOCS-1, in human monocytes exposed to GSNO. The NO donor induced significant levels of SOCS-1 mRNA and protein, 6 h and 16 h after stimulation, respectively. Monocytes stimulated with GSNO for longer periods (24 h and 48 h) failed to express IL-6 and IP-10 upon LPS challenge. In addition, and in line with previous reports of NO-mediated induction of TNF-α, we have found that exposure to this cytokine induces SOCS-1 mRNA in human monocytes. A blocking antibody against TNF-α impaired SOCS-1 expression upon GSNO treatment and re-instated IL-6 and IP-10 mRNA levels after LPS challenge in cultures pretreated with the NO donor. We conclude that NO stimulates SOCS-1 overexpression in a pathway at least partially regulated by TNF-α.
{"title":"Nitric oxide induces SOCS-1 expression in human monocytes in a TNF-α-dependent manner","authors":"M. C. González-León, Alessandra Soares-Schanoski, C. del Fresno, A. Cimadevila, V. Gómez-Piña, E. Mendoza-Barberá, Felipe García, E. Marín, F. Arnalich, P. Fuentes-Prior, E. López-Collazo","doi":"10.1177/09680519060120050501","DOIUrl":"https://doi.org/10.1177/09680519060120050501","url":null,"abstract":"In contrast to the thoroughly characterized mechanisms of positive regulation within cytokine signaling pathways, our knowledge of negative feedback loops is comparatively sparse. We and others have previously reported that IRAK-M down-regulates inflammatory responses to multiple stimuli. In particular, we could show that the nitric oxide (NO) donor, GSNO, induces IRAK-M overexpression in human monocytes. Here we study the expression of another important negative regulator of cytokine signaling, SOCS-1, in human monocytes exposed to GSNO. The NO donor induced significant levels of SOCS-1 mRNA and protein, 6 h and 16 h after stimulation, respectively. Monocytes stimulated with GSNO for longer periods (24 h and 48 h) failed to express IL-6 and IP-10 upon LPS challenge. In addition, and in line with previous reports of NO-mediated induction of TNF-α, we have found that exposure to this cytokine induces SOCS-1 mRNA in human monocytes. A blocking antibody against TNF-α impaired SOCS-1 expression upon GSNO treatment and re-instated IL-6 and IP-10 mRNA levels after LPS challenge in cultures pretreated with the NO donor. We conclude that NO stimulates SOCS-1 overexpression in a pathway at least partially regulated by TNF-α.","PeriodicalId":80292,"journal":{"name":"Journal of endotoxin research","volume":"12 1","pages":"296 - 306"},"PeriodicalIF":0.0,"publicationDate":"2006-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/09680519060120050501","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"65208556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：